1. DEFINITION AND CLASSIFICATION
- Definition: The prototype and most severe form of the Peroxisome Biogenesis Disorders (PBD).
- Classification (Zellweger Spectrum Disorders):
- Zellweger Syndrome (ZS): Most severe; neonatal onset; fatal.
- Neonatal Adrenoleukodystrophy (NALD): Intermediate severity.
- Infantile Refsum Disease (IRD): Mildest form.
2. ETIOLOGY AND GENETICS
- Inheritance: Autosomal Recessive.
- Genetic Defect: Mutations in PEX genes (Peroxin genes) required for peroxisome assembly.
- PEX1 mutation is the most common (approx. 70% of cases).
- Pathophysiology:
- Failure to import proteins into peroxisomes leads to “Ghost Peroxisomes” (empty vesicles) and functional absence of peroxisomes.
- Metabolic Consequences:
- Accumulation: Very Long Chain Fatty Acids (VLCFA), Phytanic acid, Pipecolic acid, Bile acid intermediates.
- Deficiency: Plasmalogens (essential for myelin), DHA.
- Neuronal Migration Defect: Defective neuronal migration leads to pachygyria/polymicrogyria.
3. CLINICAL FEATURES
Presents in the neonatal period with a recognizable dysmorphic phenotype.
A. Craniofacial (Dysmorphic Facies)
- “Pear-shaped head”: High, prominent forehead with flattened face.
- Large anterior fontanelle and widely split sutures.
- Eyes: Hypertelorism, epicanthal folds, shallow orbital ridges.
- Ears: Deformed ear lobes.
B. Neurologic (Severe)
- Profound Hypotonia: “Approach to a floppy infant” (often confused with Down syndrome or SMA).
- Seizures: Onset in neonatal period; often refractory.
- Sensory Deficits:
- Vision: Cataracts, glaucoma, corneal clouding, “Leopard spot” pigmentary retinopathy.
- Hearing: Sensorineural hearing loss.
- Development: Profound global developmental delay; little to no interaction.
C. Visceral (Hepato-Renal)
- Liver: Hepatomegaly with prolonged neonatal jaundice (cholestasis). Progresses to cirrhosis/fibrosis.
- Kidneys: Cortical renal cysts (microscopic or macroscopic) in >70% cases.
D. Skeletal
- Chondrodysplasia Punctata: Calcific stippling of the patella (distinctive sign) and epiphyses of long bones (seen on X-ray).
4. INVESTIGATIONS
- Biochemical Screening (Gold Standard):
- Plasma VLCFA: Markedly elevated (C26:0 and C26:1 ratio).
- RBC Plasmalogens: Reduced.
- Plasma Pipecolic Acid & Phytanic Acid: Elevated.
- Imaging:
- Ultrasound: Renal cortical cysts; Hepatomegaly.
- MRI Brain: Neuronal migration defects (pachygyria, polymicrogyria), hypomyelination, and Germinolytic cysts (cysts in the germinal matrix).
- Skeletal Survey: Stippled calcifications (chondrodysplasia punctata) in patella and hips.
- Molecular Genetics: Panel testing for PEX genes (PEX1, PEX6, PEX12, etc.).
5. DIFFERENTIAL DIAGNOSIS
- Down Syndrome (due to severe hypotonia/flat face).
- Other Peroxisomal disorders (X-linked Adrenoleukodystrophy).
- Smith-Lemli-Opitz Syndrome.
- Congenital infections (TORCH).
6. MANAGEMENT
- Curative: No cure exists. Management is strictly supportive and palliative.
- Supportive Care:
- Gastrostomy for feeding difficulties.
- Antiepileptics for seizure control.
- Vitamin K and fat-soluble vitamin supplementation (due to cholestasis/bile acid defects).
- Hearing aids and ophthalmology support.
- Experimental: Oral Cholic acid (to reduce toxic bile acid intermediates) and DHA therapy (limited efficacy).
7. PROGNOSIS
- Fatal: Death typically occurs in the first year of life (mean survival ~6 months).
- Cause of Death: Respiratory failure (aspiration/apnea), intractable seizures, or liver failure.